1. Field of the Invention
The present invention relates to novel compounds having retinoid-like biological activity. More specifically, the present invention relates to dihydrobenzofuranyl and dihydrobenzothienyl-cycloalkyl or cycloalkenyl-2,4-pentadienoic acid derivatives and to dihydrobenzofuranyl and dihydrobenzothienyl aryl or heteroaryl 2,4-pentadienoic acid derivatives having selective activity for retinoid X (RXR) receptors.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as agents to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil(copyright), diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have relatively recently been also discovered to be useful for treating type II non-insulin dependent diabetes mellitus (NIDDM).
It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARxcex1, RARxcex2 and RARxcex3, in RXR the subtypes are: RXRxcex1, RXRxcex2 and RXRxcex3. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property. Some compounds bind to one or more RAR receptor subtypes, but do not trigger the response which is triggered by agonists of the same receptors. A compound that binds to a biological receptor but does not trigger an agonist-like response is usually termed an antagonist. Accordingly, the xe2x80x9ceffectxe2x80x9d of compounds on retinoid receptors may fall in the range of having no effect at all, (inactive compound, neither agonist nor antagonist) or the compound may elicit an agonist-like response on all receptor subtypes (pan-agonist). As still another alternative a compound may be a selective agonist and/or selective antagonist of certain receptor subtypes if the compound binds to but does not activate certain receptor subtype or subtypes but elicits an agonist-like response in other receptor subtype or subtypes. A pan-antagonist is a compound that binds to all known retinoid receptors but does not elicit an agonist-like response in any of the receptors.
Recently a two-state model for certain receptors, including the above-mentioned retinoid receptors, have emerged. In this model, an equilibrium is postulated to exist between inactive receptors and spontaneously active receptors which are capable of coupling with a G protein in the absence of a ligand (agonist). In this model, so-called xe2x80x9cinverse agonistsxe2x80x9d shift the equilibrium toward inactive receptors, thus bringing about an overall inhibitory effect. Neutral antagonists do not effect the receptor equilibrium but are capable of competing for the receptors with both agonists (ligands) and with inverse agonists. U.S. Pat. No. 5,877,207 titled xe2x80x9cSynthesis and Use of Retinoid Compounds Having Negative Hormone and/or Antagonist Activitiesxe2x80x9d describes the foregoing two-state model and the use of retinoid antagonist and negative hormones in detail.
Among the scientific publications Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 334-335, 354 and 324-356 is of special interest as an overview of the prior art on the subject.
The following is a list of United States and foreign patents and publications which disclose compounds having structural similarity to the compounds of the present invention, or disclose compounds having retinoid agonist, antagonist or inverse agonist like biological activity having a benzofuran, indole, benzothiophene or closely related moiety or a pentadienoic acid moiety: U.S. Pat. Nos. 6,172,115; 6,048,873; 6,034,110; 5,917,082; 6,093,838; 5,675,033; 6,147,224; 5,728,846; 5,324,840; 5,344,959; 5,466,861; WO 96/05165; WO 93/21162; EPO 0 098 591; Janusz et al. J. Med. Chem. 1998 41 1124-1137; Iida et al. Tetrahedron Letters 35, 1982 p 3591-3594; Vuligonda et al. Bioorg. Med. Chem. Lett. 6 (2) 213-8, 1996.
The present invention relates to compounds of Formula 1
where X is O or S;
Y is a bivalent cycloalkyl or cycloalkenyl radical optionally substituted with one to four R4 groups, the cycloalkenyl radical having 5 or 6 carbons and one double bond, or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups optionally substituted with 1 to 4 R4 groups;
R1 is independently H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8 carbons;
R2 is independently H, alkyl of 1 to 8 carbons, or fluoroalkyl of 1 to 8 carbons;
R3 is hydrogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, halogen, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10 carbons; NO2, NH2, NHCO(C1-C6 alkyl, NHCO(C1-C6)alkenyl, NR1H or N(R1)2, benzyloxy, C1-C6alkyl-substituted benzyloxy, hydroxyalkyl of 1 to 10 carbons, or
R3 is selected from the groups shown below, 
R4 is H, halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10 carbons;
m is an integer having the values of 0 to 3;
r is an integer having the values of 1 to 10;
s is an integer having the values 1 to 4;
t is an integer having the values 1 to 5; 
represents a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatoms selected from the group consisting of N, S and O;
B is COOH or a pharmaceutically acceptable salt thereof, COOR8, COOCH2COR7, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CH(OR13O), xe2x80x94COR7, CR7 (OR12)2, CR7 (OR13O), where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, CH2OCOR12, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R11 is alkyl of 1 to 6 carbons, phenyl or lower alkylphenyl, R12 is alkyl of 1 to 6 carbons, and R13 is divalent alkyl radical of 2-5 carbons.
In a second aspect, this invention relates to the use of the compounds of Formula 1 for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The compounds are also useful for the prevention and treatment of metabolic diseases such as type II diabetes and diabetes mellitus and for prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other comeopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as agents to increase the level of circulating tissue plasminogen activator (TPA). Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with Human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil(copyright), diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
Generally speaking, the second aspect of the invention relates to the use of the novel compounds to prevent or treat diseases and conditions which are responsive to compounds that promote the expression of or bind to receptors belonging to the steroid or thyroid receptor superfamily.
This invention also relates to a pharmaceutical formulation comprising a compound of Formula 1 in admixture with a pharmaceutically acceptable excipient, said formulation being adapted for administration to a mammal, including a human being, to treat or alleviate the conditions which were described above as treatable by retinoids.
Assays of Retinoid-Like Biological Activity
A classic measure of retinoic acid activity involves measuring the effects of retinoic acid on ornithine decarboxylase. The original work on the correlation between retinoic acid and a decrease in cell proliferation was done by Verma and Boutwell, Cancer Research, 1977, 37, 2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be modulated. Although all cases for ODC activity increases are unknown, it is known that 12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. An assay essentially following the procedure set out in Cancer Research: 1662-1670,1975 may be used to demonstrate inhibition of TPA induction of ODC by compounds of this invention. xe2x80x9cIC60xe2x80x9d is that concentration of the test compound which causes 60% inhibition in the ODC assay. By analogy, xe2x80x9cIC80xe2x80x9d, for example, is that concentration of the test compound which causes 80% inhibition in the ODC assay.
Other assays described below, measure the ability of the compounds of the present invention to bind to, and/or activate various retinoid receptor subtypes. When in these assays a compound binds to a given receptor subtype and activates the transcription of a reporter gene through that subtype, then the compound is considered an agonist of that receptor subtype. Conversely, a compound is considered an antagonist of a given receptor subtype if in the below described co-tranfection assays the compound does not cause significant transcriptional activation of the receptor regulated reporter gene, but nevertheless binds to the receptor with a Kd value of less than approximately 1 micromolar. In the below described assays the ability of the compounds to bind to RARxcex1, RARxcex2, RARxcex3, RXRxcex1, RXRxcex2 and RXRxcex3 receptors, and the ability or inability of the compounds to activate transcription of a reporter gene through these receptor subtypes can be tested. These assays are expected to demonstrate that the compounds of the present invention act as agonists of one or more of the above-described receptors. Because of the complex distribution of the different retinoid receptors in various organs of the mammalian body subtype selective agonists may lend themselves to particularly useful therapeutic applications and may avoid serious side effects of conventional retinoid drugs.
As far as specific assays are concerned to demonstrate the activities of the compounds of the present invention, a chimeric receptor transactivation assay which tests for agonist-like activity in the RARxcex1, RARxcex2, RARxcex3, RXRxcex1, receptor subtypes, and which is based on work published by Feigner P. L. and Holm M (1989) Focus, 112 is described in detail in U.S. Pat. No. 5,455,265. The specification of U.S. Pat. No. 5,455,265 is hereby expressly incorporated by reference.
A holoreceptor transactivation assay and a ligand binding assay which measure the antagonist/agonist like activity of the compounds of the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in published PCT Application No. WO WO93/11755 (particularly on pages 30-33 and 37-41) published on Jun. 24, 1993, the specification of which is also incorporated herein by reference. A detailed experimental procedure for holoreceptor transactivations has been described by Heyman et al. Cell 68, 397-406, (1992); Allegretto et al. J. Biol. Chem. 268, 26625-26633, and Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp 319-349, Raven Press Ltd., New York, which are expressly incorporated herein by reference. The results obtained in this assay are expressed in EC50 numbers, as they are also in the chimeric receptor transactivation assay. The results of ligand binding assay are expressed in Kd numbers. (See Cheng et al. Biochemical Pharmacology Vol. 22 pp 3099-3108, expressly incorporated herein by reference.)
Still another transactivation assay, the xe2x80x9cPGR assayxe2x80x9d is described in the publication Klein et al. J. Biol. Chem. 271, 22692-22696 (1996) which is expressly incorporated herein by reference, and a detailed description is also provided below. The results of the PGR assay are also expressed in EC50 numbers (nanomolar concentration).
CV-1 cells (4xc3x97105 cells/well) were transiently transfected with the luciferase reporter plasmid MTV-4 (R5G)-Luc (0.7 ug/well) containing four copies of the R5G retinoid DNA response element along with the RXRxcex1 expression plasmid pRS-hRXRxcex1 (0.1 ug/well) and one of the RAR-P-GR expression plasmids (0.05 ug/well) in 12 well plates via calcium phosphate precipitation Chen et al. (1987) Mol. Cell. Biol. 7, 2745-2752 as described by Klein et al. in J. Biol. Chem. 271, 22692, referenced above. The three different RAR-P-GR expression plasmids, pRS-RARxcex1-P-GR, pcDNA3-RARxcex2-P-GR and pcDNA3-RARxcex3-P-GR, express RARxcex1, RARxcex2 and RARxcex3 receptors, respectively, which contain modified DNA binding domains such that their xe2x80x9cP-boxesxe2x80x9d have been altered to that of the glucocorticoid receptor. These RAR-P-GR receptors bind to DNA as heterodimeric complexes with RXR. Specifically, the RAR-P-GR receptors bind retinoic acid response elements designated R5G, comprised of two RAR half sites (nucleotide sequence 5xe2x80x2-GGTTCA-3xe2x80x2) separated by 5 base pairs in which the 3xe2x80x2-half site has been modified to that of a glucocorticoid receptor half site, 5xe2x80x2-AGAACA-3xe2x80x2. To allow for various in transfection efficiency a xcex2-galactosidase expression plasmid (0.01 ug/well) was used as an internal control. Alternatively, the assay was performed in a 96-well microtiter plate format (5000 cells/well) in a manner which was identical to that described above except ⅕ of the amount of the DNA-calcium phosphate precipitant (20 xcexcl instead of 100 xcexcl) was applied to each well. Eighteen hours after introduction of the DNA precipitants, cells were rinsed with phosphate buffered saline (PBS) and fed with D-MEM (Gibco-BRL) containing 10% activated charcoal extracted fetal bovine serum (Gemini Bio-Products). Cells were treated for 18 hours with the compounds indicated in the figures. After rinsing with PBS cells were lysed and luciferase activity was measured as previously described in de Wet (1987) Mol. Cell. Biol. 7, 725-737. Luciferase values represent the meanxc2x1SEM of triplicate determinations normalized to xcex2-galactosidase activity.
Table 1 discloses the activity of certain exemplary compounds of the invention in the above-described chimeric receptor transactivation and ligand binding assays. Table 1 also discloses the most preferred compounds of the invention, shown in their free carboxylic acid form. In the chimeric receptor transactivation assay the compounds were essentially inactive in activating RARxcex1, RARxcex2 and RARxcex3 receptors.
As it can be seen from the foregoing assay results, the compounds of the invention are specific or selective agonists of RXR receptors.
Modes of Administration
The compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations. Thus, in the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, by Remington""s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection. Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention. A therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient""s susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg of body weight per day would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
Definitions
The term alkyl refers to and covers any and all groups which are known as normal alkyl, branched-chain alkyl, cycloalkyl and also cycloalkyl-alkyl. The term alkenyl refers to and covers normal alkenyl, branch chain alkenyl and cycloalkenyl groups having one or more sites of unsaturation. Similarly, the term alkynyl refers to and covers normal alkynyl, and branch chain alkynyl groups having one or more triple bonds.
Unless specified otherwise, lower alkyl means the above-defined broad definition of alkyl groups having 1 to 6 carbons in case of normal lower alkyl, and as applicable 3 to 6 carbons for lower branch chained and cycloalkyl groups. Lower alkenyl is defined similarly having 2 to 6 carbons for normal lower alkenyl groups, and 3 to 6 carbons for branch chained and cyclo-lower alkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl groups.
The term xe2x80x9cesterxe2x80x9d as used here refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters. Where B of Formula 1 is xe2x80x94COOH, this term covers the products derived from treatment of this function with alcohols or thiols preferably with aliphatic alcohols having 1-6 carbons. Where the ester is derived from compounds where B is xe2x80x94CH2OH, this term covers compounds derived from organic acids capable of forming esters including phosphorous based and sulfur based acids, or compounds of the formula xe2x80x94CH2OCOR11 where R11, is a variable as defined above in connection with Formula 1.
Unless stated otherwise in this application, preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols. Also preferred are the phenyl or lower alkyl phenyl esters.
The term amides has the meaning classically accorded that term in organic chemistry. In this instance it includes the unsubstituted amides and all aliphatic and aromatic mono- and di-substituted amides. Unless stated otherwise in this application, preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms. Particularly preferred amides are those derived from substituted and unsubstituted lower alkyl amines. Also preferred are mono- and disubstituted amides derived from the substituted and unsubstituted phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred.
Acetals and ketals include the radicals of the formula-CK where K is (xe2x80x94OR)2. Here, R is lower alkyl. Also, K may be xe2x80x94OR7Oxe2x80x94 where R7 is lower alkyl of 2-5 carbon atoms, straight chain or branched.
A pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri-acid may also be used.
The compounds of the present invention are capable of existing as trans and cis (E and Z) isomers relative to olephinic double bonds, cycloalkyl rings and particularly and in case of the preferred compounds relative to the cyclopropane ring. The invention covers trans as well as cis isomers relative to each center that gives rise to such isomerism. However for certain preferred compounds specific orientation of substituents relative to a double bond or the ring is indicated in the name of the respective compound, and/or by specific showing in the structural formula of the orientation of the substituents relative to the double bond or ring.
Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well.
Reaction Scheme 1 discloses a general and nevertheless presently preferred synthetic route to a class of preferred compounds of the invention where the variable Y of Formula 1 represents a bivalent cyclopropyl radical, the variable X is O or S (dihydrobenzofuran and dihydrobenzothiophen derivatives) and where the 2,2xe2x80x2 position of dihydrobenzofuran or of dihydrobenzothiophen is unsubstituted. Referring now to this scheme, the starting compound in this synthetic route is a compound of Formula 2, which is a 4-bromo (or other halogeno)-phenol or corresponding thiophenol substituted with the R3 group, or groups. (The variable R3 and m are defined as in connection with Formula 1.) Compounds of Formula 2 are available commercially and/or can be prepared in accordance with the chemical literature, or by such modifications of known synthetic procedures which are readily apparent to those skilled in the art. In the ensuing description the scheme is described with primary reference to the preparation of dihydrobenzofuran compounds because these are the most preferred embodiments, however it should be kept in mind that the corresponding dihydrobenzothiophen derivatives can be prepared in the same manner with intermediates where the variable X is S (sulfur).
Thus, the 4-bromophenol derivative of Formula 2 is reacted with a 3-chloro-2-methylpropene derivative of Formula 3. In Formula 3 the variable R2 is defined as in connection with Formula 1 and the variable R2(-1) is defined as the variable R2 minus one methylene group and can be just a H. Compounds of Formula 3 are available commercially and/or can be prepared in accordance with the chemical literature, or by such modifications of known synthetic procedures which are readily apparent to those skilled in the art. An example of a reagent of Formula 3 which is utilized for the synthesis of several preferred compounds of the invention is 3-chloro-2-methylpropene. The reaction between the 4-bromophenol derivative of Formula 2 and the 3-chloro-2-methylpropene derivative of Formula 3 is conducted under Friedel Crafts conditions (e.g. in concentrated sulfuric acid) to provide 4-bromo-2-(2-chloro-1,1-dialkyl-ethyl)phenol (or thiophenol) compounds of Formula 4. In the most preferred compounds of the invention the R2 groups are methyl. The compound of Formula 4 is ring closed with strong base in an aprotic solvent (sodium hydride in tetrahydrofuran (THF)) to give the 5-bromo-3,3-dialkyl-2,3-dihydro-benzofuran derivative of Formula 5.
The 5-bromo-3,3-dialkyl-2,3-dihydro-benzofuran derivative of Formula 5 is then reacted with t-butyllithium in n-pentane and trimethyl borate is added to the resulting solution to give a 3,3-dialkyl-2,3-dihydro-benzofuran-5-boronic acid derivative or the corresponding dihydrobenzothiophene derivative of Formula 6. The 3,3-dialkyl-2,3-dihydro-benzofuran-5-boronic acid derivative of Formula 6 is heated with 3-iodo-but-2 (Z)-ene-ol of Formula 7, in the presence of tetrakis(triphenyl-phosphine)palladium(0) (Pd(PPh3)4) and potassium carbonate in a mixture of methanol, toluene and water under an argon atmosphere. Although the reaction scheme illustrates 3-iodo-but-2 (Z)-ene-ol because this reagent is used for the synthesis of the presently preferred compounds of the invention, it should be understood that further alkyl substituted derivatives of 3-iodo-but-2 (Z)-ene-ol can also be used to provide alternative embodiments of this class of preferred compounds of the invention where the cyclopropyl ring is substituted with alkyl groups other than in the below shown preferred embodiments.
After work-up with sodium carbonate a 3,3-dialkyl-5-(3-hydroxy-1-methyl-prop-(1Z)-enyl)-2,3-dihydro-benzofuran derivative of Formula 8 is obtained. The compound of Formula 8 is converted into the 3,3-dialkyl-5-[(1S,2 S)-3-hydroxy-1,2-methano-1-methyl-propyl]-2,3-dihydro-benzofuran derivative of Formula 9 by treatment with diethylzinc and diiodomethane in anhydrous dichloromethane in the presence of (4S-trans)-2-butyl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl[1,3,2]dioxaborolane-[4,5]dicarboxamide (Formula 10) which can be prepared in accordance with the teaching of J. Amer. Chem. Soc. 1998, 120, 11943 (incorporated herein by reference). As is known, the cyclopropylation reaction with diiodomethane preserves the cis or trans stereochemistry of the double bond to which the xe2x80x9cCH2xe2x80x9d moiety is added. Thus, depending on the cis or trans nature of the reagent of Formula 7 either cis or trans stereochemistry relative to the cyclopropane ring can be obtained. Reaction Scheme 1 shows only one such compound (Formula 9) which is cis. The levorotatory reagent (4S,-trans)-2-butyl-N,N,N,N-tetramethyl[1,3,2-]-dioxaborolane-[4,5]dicarboxamide causes the reaction to provide a mixture of enantiomers wherein one of the two enantiomers predominates but is not the exclusive product. In order to obtain predominantly the other enantiomer, the reagent derived from (R1R)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethlyl tartaramide would be used. In the next few steps of the synthesis of this class of preferred compounds of the invention the compound of Formula 9 is further resolved to provide a predominantly or substantially pure optical isomer. The resolution is conducted through esterification with (1S)-camphanic chloride (Formula 11) to give the corresponding (1S)-camphanate ester of Formula 12 which is thereafter saponified to provide the predominantly or substantially optically pure 3,3-dialkyl-5-[(1S,2S)-3-hydroxy-1,2-methano-1-methyl-propyl]-2,3-dihydro-benzofuran derivative of Formula 13.
The predominantly or substantially optically pure 3,3-dialkyl-5-[(1S,2S)-3-hydroxy-1,2-methano-1-methyl-propyl]-2,3-dihydro-benzofuran derivative of Formula 13 is then oxidized to the xe2x80x9caldehyde levelxe2x80x9d by treatment with molecular sieves powder, tetra-n-propylammoniumperruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) to provide a 3,3-dialkyl-5-[(1S,2S)-1,2-methano-1-methyl-3-oxo-propyl]-2,3-dihydro-benzofuran derivative of Formula 14. The aldehyde of Formula 14 is subjected to a Horner Emmons reaction with a diethylphosphono reagent of Formula 15 wherein the R1 group is defined as in connection with Formula 1. A preferred example of the reagent of Formula 15 is ethyl-diethylphosphono-3-methyl-2 (E)butenoate (also known as methyl-3-methyl-4-diethylphosphonocrotonate) which can be obtained in accordance with the chemical literature (J. Org. Chem. 1974, Volume 39 page 821). The resulting dihydrobenzofuranyl-cyclopropyl-pentadienoic acid ester derivatives or the corresponding dihydrothiophene derivatives of Formula 16 are compounds within the scope of the present invention. These compounds are also saponified to provide the free pentadienoic acid derivatives (or their salts) of Formula 17. 
The compounds shown in Reaction Scheme 1 by Formulas 16 and 17 can be converted into further homologs and derivatives still within the scope of the invention, by such reactions as esterification, saponification, homologation, reduction to aldehyde or alcohol stage and the like, which per se are well known in the art. These reactions usually involve transformations of the group B in Formula 1, but are not necessarily limited to those. Some of the known and published general principles and synthetic methodology employed in the transformations of the B group are briefly described below.
Carboxylic acids are typically esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride. Alternatively, the carboxylic acid can be condensed with the appropriate alcohol in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP). The ester is recovered and purified by conventional means. Acetals and ketals are readily made by the method described in March, xe2x80x9cAdvanced Organic Chemistry,xe2x80x9d 2nd Edition, McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers and esters, acetals or ketals by known methods such as those described in McOmie, Plenum Publishing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley and Sons, 1981.
The acids and salts derived from compounds of the invention are readily obtainable from the corresponding esters. Basic saponification with an alkali metal base will provide the acid. For example, an ester of the invention may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about a three molar excess of base, for example, lithium hydroxide or potassium hydroxide. The solution is stirred for an extended period of time, between 15 and 20 hours, cooled, acidified and the hydrolysate recovered by conventional means.
The amide may be formed by any appropriate amidation means known in the art from the corresponding esters or carboxylic acids. One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine. For example, the ester is treated with an alcoholic base solution such as ethanolic KOH (in approximately a 10% molar excess) at room temperature for about 30 minutes. The solvent is removed and the residue taken up in an organic solvent such as diethyl ether, treated with a dialkyl formamide and then a 10-fold excess of oxalyl chloride. This is all effected at a moderately reduced temperature between about xe2x88x9210 degrees and +10 degrees C. The last mentioned solution is then stirred at the reduced temperature for 1-4 hours, preferably 2 hours. Solvent removal provides a residue which is taken up in an inert organic solvent such as benzene, cooled to about 0 degrees C. and treated with concentrated ammonium hydroxide. The resulting mixture is stirred at a reduced temperature for 1-4 hours. The product is recovered by conventional means.
Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 2nd Edition, McGraw-Hill Book Company), then reducing the acid chloride with sodium borohydride (March, ibid, pg. 1124), which gives the corresponding alcohols. Alternatively, esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylating these alcohols with appropriate alkyl halides under Williamson reaction conditions (March, ibid, pg. 357) gives the corresponding ethers. These alcohols can be converted to esters by reacting them with appropriate acids in the presence of acid catalysts or dicyclohexylcarbodiimide and dimethylaminopyridine.
Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D., Tetrahedron, 1978, 34, 1651).
Acetals or ketals can be prepared from the corresponding aldehyde or ketone by the method described in March, ibid, p 810.
Reaction Scheme 2 discloses a general and nevertheless presently preferred synthetic route to a class of preferred compounds of the invention where the variable Y of Formula 1 represents a bivalent 5 or 6 membered cycloalkyl radical, the variable X is O or S (dihydrobenzofuran and dihydroben N1 zothiophen derivatives) and where the 2,2xe2x80x2 position of dihydrobenzofuran or of dihydrobenzothiophen is unsubstituted. Referring now to this scheme, one starting compound in this synthetic route is a compound of Formula 6, which can be obtained as described above in connection with Reaction Scheme. The other starting material is a bromo (or other halogeno) substituted cyclohexane or cyclopentane carboxylic acid ester of Formula 18 which may have additional R4 substituents (R4 is defined as in connection with Formula 1 and p in this and the ensuing schemes is defined as an integer having the values of 0 to 4). The bromo (or other halogeno) group and the carboxylic acid ester group are in adjacent (1,2) position in the compounds of Formula 18. Compounds of Formula 18 can be obtained in accordance with the chemical literature, for example by following the procedures described by Cook in J.Chem.Soc.; 1934; 946, 954 and by Ives in J.Chem.Soc.; 1943; 513, 516, or by such modifications of these chemical procedures which become readily apparent to those skilled in the art. The Cook and Ives publications are hereby expressly incorporated by reference.
The compounds of Formula 6 and of Formula 18 are reacted by heat in the presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) and sodium carbonate in a mixture of methanol, toluene and water under an argon atmosphere to provide the dihydrobenzofuranyl or dihydrobenzothienyl-cycloalkylcarboxylic acid esters of Formula 19. The dihydrobenzofuranyl or dihydrobenzothienyl-cycloalkylcarboxylic acid esters of Formula 19 are then reduced to the corresponding aldehyde level by treatment with DIBAL-H (diisobutyl aluminum hydride) in the presence of tetra-n-propylammonium-perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO), providing the dihydrobenzofuranyl or dihydrobenzothienyl-cycloalkyl-aldehydes of Formula 20. The aldehyde of Formula 20 is thereafter coupled with the diethylphosphono reagent of Formula 15 in a Horner Emmons reaction to give the dihydrobenzofuranyl-cycloalkyl-pentadienoic acid ester derivatives or the corresponding dihydrothiophene derivatives of Formula 21. The compounds of Formula 21 are within the scope of the present invention and can be saponified to provide the free pentadienoic acid derivatives (or their salts) of Formula 22 or can be converted into further derivatives within the scope of the invention, as is described in connection with Reaction Scheme 1. 
Reaction Scheme 3 discloses a general and nevertheless presently preferred synthetic route to a class of preferred compounds of the invention where the variable Y of Formula 1 represents a bivalent 5 or 6 membered cycloalkenyl radical having a single double bond in the ring and where the variable X is O or S (dihydrobenzofuran and dihydrobenzothiophen derivatives) and where the 2,2xe2x80x2 position of dihydrobenzofuran or of dihydrobenzothiophen is unsubstituted. Referring now to this scheme, the starting compound in this synthetic route is a compound of Formula 23 which is a bromo (or other halogeno) substituted cyclohexene or cyclopentene carbaldehyde which may have additional R4 substituents (R4 is defined as in connection with Formula 1). The bromo (or other halogeno) group and the aldehyde group are in adjacent (1,2) position in the compounds of Formula 23. Compounds of Formula 23 can be obtained in accordance with the chemical literature, for example by following the procedures described by Arnold et al., Collect. Czech. Chem. Commun., 26, 1961, 3059-3073, or by such modifications of these chemical procedures which are readily apparent to those skilled in the art. The Arnold et al. publication is hereby expressly incorporated by reference.
The aldehyde of Formula 23 is reacted with the diethylphosphono reagent of Formula 15 in a Horner Emmons reaction to give a bromo substituted cycloalkenyl pentadioenoic acid ester of Formula 24. The compound of Formula 24 is then reacted with the 3,3-dialkyl-2,3-dihydro-benzofuran-5-boronic acid derivative (or corresponding dihydrobenzothienyl derivative) of Formula 6 in the presence of tetrakis(triphenylphosphine)-palladium(0) (Pd(PPh3)4) and sodium carbonate in a mixture of methanol, toluene and water under an argon atmosphere to provide the dihydrobenzofuranyl or dihydrobenzothienyl-cycloalkenyl-pentadienoic acid esters of Formula 25. The compounds of Formula 25 are within the scope of the present invention and can be saponified to provide the free pentadienoic acid derivatives (or their salts) of Formula 26 or can be converted into further derivatives within the scope of the invention, as is described in connection with Reaction Scheme 1. 
Reaction Scheme 4 discloses a general and nevertheless presently preferred synthetic route to a class of preferred compounds of the invention where the variable Y of Formula 1 represents a bivalent phenyl or a 5 or 6 heteroaryl radical and where the variable X is O or S (dihydrobenzofuran and dihydrobenzothiophen derivatives) and where the 2,2xe2x80x2 position of dihydrobenzofuran or of dihydrobenzothiophen is unsubstituted. The aryl or heteroryl group is defined as in connection with Formula 1, although for the sake of simplifying the description in this scheme the formulas are drawn and the description is provided primarily with reference to the phenyl group only. Referring now to this scheme, the starting compound in this synthetic route is a compound of Formula 27 which is a bromo (or other halogeno) substituted aryl carbaldehyde (shown as benzaldehyde) which may have additional R4 substituents (R4 is defined as in connection with Formula 1). Such bromo (or other halogeno) substituted aryl carbaldehyde compounds can be obtained in accordance with the chemical patent and scientific literature or by such modifications of the literature procedures which are readily apparent to those skilled in the art. An example for a compound of Formula 27 is 2-bromobenzaldehyde which is available commercially Other examples for the reagent of Formula 27 are 3-bromopyridine-2-carboxaldehyde, 3-bromothiophene-2-carboxaldehyde, 3-bromofuran-2-carboxaldehyde, 2-bromopyridine-3-carboxaldehyde, 2-bromothiophene-3-carboxaldehyde and 2-bromofuran-3-carboxaldehyde.
The bromo-substituted aryl aldehyde of Formula 27 is reacted with the diethylphosphono reagent of Formula 15 in a Horner Emmons reaction to give a bromo substituted phenyl (or other aryl or heteroaryl) pentadioenoic acid ester of Formula 28. Reaction of the compound of Formula 28 with the 3,3-dialkyl-2,3-dihydro-benzofuran-5-boronic acid derivative (or corresponding dihydrobenzothienyl derivative) of Formula 6 in the presence of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) and sodium carbonate in a mixture of methanol, toluene and water under an argon atmosphere provides the dihydrobenzofuranyl or dihydrobenzothienyl-phenyl (or heteroaryl) pentadienoic acid esters of Formula 29. The compounds of Formula 29 are within the scope of the present invention and can be saponified to provide the free pentadienoic acid derivatives (or their salts) of Formula 30 or can be converted into further derivatives within the scope of the invention, as is described in connection with Reaction Scheme 1.
With reference to the symbol Y in Formula 1 the preferred compounds of the invention are those where Y is cyclopropyl. Compounds are also preferred where Y is a bivalent phenyl, naphthyl, pyridyl, thienyl or furyl radical, 5 or 6 membered cycloalkyl or 5 or 6 membered cycloalkenyl, substituted on adjacent carbons respectively with the pentadienoic acid and the dihydrobenzofuranyl or dihydrobenzothienyl groups. In most of the presently preferred compounds of the invention the R4 substituent on the cyclopropyl group is methyl, and there is only one methyl substituent on the cyclopropyl ring, however in some other preferred compounds the cyclopropyl group has no methyl substituent.
The compounds preferably are dihydrobenzofuran derivatives, so that the variable X is preferably oxygen (O).
The B group of the preferred compounds is COOH or COOR8, where R8 is defined as above. Even more preferably R8 is alkyl of 1 to 6 carbons, most preferably ethyl, or the compound is a carboxylic acid, or a pharmaceutically acceptable salt thereof.
R1 is preferably H or an alkyl group of 1 to 6 carbons. Even more preferably R1 is H or methyl.
The R2 groups are preferably H or alkyl of 1 to 6 carbons, more preferably alkyl. In the most preferred compounds of the invention both R2 groups are methyl.
The Rxe2x80x22 groups are also preferably H or alkyl of 1 to 6 carbons, most preferably H.
A great number of R3 groups are preferred in the compounds of the invention, particularly when the R3 group occupies the 7 position of the dihydrobenzofuran nucleus, as is shown in Table 1. Among the preferred R3 groups are: H, halogen, particularly Br, alkyl of 1 to 10 carbons, cyclohexyl, hydroxyalkyl, and an alkyl group containing an oxo function, phenyl, phenyl substituted with halogen particularly with a fluoro group, phenyl substituted with one or two alkyl groups each having 1 to 10 carbons, phenyl substituted with an alkoxy group, or phenylmethyl. The presently most preferred compounds of the invention are shown as free carboxylic acids in Table 1, however it should be kept in mind that pharmaceutically acceptable salts and C1-6 alkyl esters, particularly ethyl esters of these compounds are also preferred.